Attention deficit hyperactivity disorder (ADHD) is a disorder especially prevalent in children and is associated with an increase in motor activity and a reduction in attention. It is a behavioural syndrome with a neurological base and a strong genetic component. It is a very prevalent disorder affecting between 5% and 10% of the infant-juvenile population, being 3 times more frequent in males. No differences have been demonstrated between geographic areas, cultural groups or socio-economic levels. It represents between 20% and 40% of referrals to infant-juvenile psychiatric services.
This is a neurological disorder of behaviour characterised by moderate or severe distraction, short attention span, restlessness, emotional instability and impulsive behaviours. Although it was initially recognised in childhood, it has been recognised to have a chronic nature since it persists and manifests beyond adolescence. Long term studies have demonstrated that between 60% and 75% of children with ADHD continue to present symptoms in adult life.
The main traits of ADHD are firstly difficulty in maintaining concentration (attention deficit), especially in circumstances of low stimulation and secondly lack of inhibition or cognitive control over impulses, frequently associated with motor restlessness (hyperactivity-impulsiveness). These two sets of signs can appear separately or together.
The symptoms of ADHD fall into three groups:                Lack of attention (inattention)        Hyperactivity        Impulsive behaviour (impulsiveness)        
Some children with ADHD have the type of disorder with mainly lack of attention. Others can have a combination of various types. Those children with the lack of attention type of disorder are less disturbed and they are less likely to be diagnosed with ADHD.
The symptoms of lack of attention are:                Not paying careful attention to details or making errors due to carelessness in school work.        Having difficulty in maintaining attention in tasks or games.        Not seeming to listen when talked to directly.        Not following instructions and not finishing school work, homework or other obligations at work.        Having difficulty in organising tasks and activities.        Avoiding or not wanting to commit to tasks that require continuous mental effort (such as school work).        Frequently losing toys, school work, pencils, books or tools necessary for tasks and activities.        Being easily distracted.        Often seeing to be forgetful in daily activities        
The symptoms of hyperactivity are:                Playing with hands or feet and fidgeting when seated.        Leaving the chair when expected to remain seated.        Excessive running and climbing in inappropriate situations.        Having difficulty in playing quietly.        Often talking too much, always “on the go” or acting as if “driven by an engine”.        
The symptoms of impulsiveness are:                Replying before hearing the whole question.        Having difficulty in waiting their turn.        Butting in or interrupting others (disrupting conversations or games).        
Too often, difficult children are incorrectly classified as children suffering attention deficit hyperactivity disorder and on the other hand, many children with the disorder remain undiagnosed. In either case, they often have much difficulty with learning and mood swings. The American Academy of Pediatrics (AAP) has published guidelines to help to clarify the matter.
The diagnosis is based on very specific symptoms that must be present in more than one scenario:                Children must have at least 6 symptoms of attention deficit or 6 symptoms of hyperactivity and impulsiveness, with some symptoms present before the age of 7.        The symptoms must be present for at least 6 months, be observed in two or more scenarios and not be caused by another problem.        The symptoms must be so serious that they cause significant difficulty in many scenarios, including in the home, school and relations with friends.        
In older children, ADHD is in partial remission when there are still symptoms, but then it does not meet the complete definition of the disorder.
The child must be submitted to an evaluation by a doctor if suspected to have ADHD and this may include:                Questionnaires for the parents and teachers (for example, Connors, Burks).        Psychological evaluation of the child and the family, including an intelligence quotient test and psychological tests.        Mental, nutritional, physical, psycho-social and comprehensive development evaluation.        
At the moment, there are no laboratory tests that have been established as diagnostic in the clinical assessment of attention deficit hyperactivity disorder.
Depression, lack of sleep, learning difficulties, tics and behavioural problems may be confused with, or appear along with ADHD. When children are suspected of suffering from this disorder, they must be carefully examined by a doctor to rule out other possible conditions or reasons for their behaviour.
The symptoms of ADHD express a biological problem and is currently dealt with by pharmacological treatment, which is still the most important therapeutic approach. Common treatments are paradoxically based on stimulants, which have been observed to improve symptoms. Among them are caffeine and nicotine, which are sometimes used by adolescents and adults for self-medication. The first report endorsing the use of psychostimulants, dating back to 1937, is when Charles Bradley established the efficacy and safety of amphetamine sulphate to treat hyperactive children.
Currently, the most widely used substances in the United States are methylphenidate (active ingredient behind the Ritalin trade name) and DL-amphetamine (Adderall), followed by dexamphetamine (Dexedrine) and methamphetamine. Other second line psychostimulants for ADHD treatment are pemoline (Cylert) and modafinil (Modiodal). In recent years, the drugs with immediate effect tend to be replaced by other preparations that, using the same active ingredients, achieve a longer lasting effect, improving the children's quality of life, especially schoolchildren. The use of many of these drugs has been questioned due to the side effects that occur.
Although stimulants are the first line therapy for this disorder, some antidepressants such as fluoxetine (Prozac), bupropion (Wellbutrin), venlafaxine (Effexor) and desipramine have shown some value, especially when ADHD occurs with co-morbidities such as major depressive disorder or anxiety disorders (for example generalised anxiety disorder).
Clinical investigations are under way seeking to extend the application of adrenergic active ingredients, non-stimulants, such as atomoxetine (Strattera, a synaptic norepinephrine reuptake inhibitor) and alpha-adrenergic agonists such as clonidine and guanfacine. Of these three, only atomoxetine has been approved for this indication. Launched in 2002, atomoxetine is proposed as a second-line drug when stimulants are not well tolerated. Treatment success rate does not exceed that of traditional drugs. Neither does it have a very benign side effect profile. Being a new substance, complete information regarding the expected long term effects are lacking. Recently, atomoxetine has been related to increased risks of liver toxicity, although the evidence for this is preliminary. Added to this, on 28 Sep. 2005, a warning was given by the Health Agency of Canada linking the use of this drug with possible phenomena of depersonalisation, self-harm and suicidal thoughts among adult and paediatric patients.
As with other psycho-pathologies where the treatment is predominantly pharmacological, both the diagnosis of ADHD and the viability of medical treatment have been openly rejected by supporters of the so-called anti-psychiatry movement.
Psychological treatment of associated behavioural problems is also accepted. These types of interventions are complementary to pharmacological treatment and normally seek to reduce disruptive behaviours of children in various environments by cognitive-behavioural type therapies. Similarly, educational psychology counselling may be advisable for learning difficulties that often appear in a large proportion of subjects with ADHD. Currently, positive development therapies are being developed in children, trying to reinforce the potential of young people through sport and group dynamics. Various researchers have developed reinforcement models through token economies with groups of children with ADHD and have shown that when well conducted, they give better results than individual therapy. In this way, aspects such as self-esteem and social skills can be explored.
Histamine [2-(4-Imidazolyl)ethylamine] is an important mediator of many biological processes including inflammation, gastric acid secretion, neuromodulation and regulation of the immune function. Because of its strong pharmacological activity, even at very low concentrations, synthesis, transport, storage, release and degradation of histamine must be very carefully controlled to prevent undesirable reactions. High concentrations of free histamine in circulation have been described to trigger unwanted effects such as headaches, stuffy or runny nose, respiratory tract obstructions, tachycardia, gastric and intestinal ailments, swelling of eyelids, skin rashes, reduced blood pressure, bronchospasm, etc.
Histamine is produced by the human body and stored in an inactive form in the metachromatic granules of mast cells and basophilic leukocytes, where it is available for immediate release. The highest histamine concentrations are measured in the lungs. After release, histamine is an extraordinarily strong mediator in a wide range of physiological and pathophysiological processes, frequently via interaction with cytokines.
Histamine can also enter the human body from the outside as it is generated by microbiological action in the course of processing foods and therefore is present in substantial amounts in many foods and fermented drinks such as wine, champagne and a large proportion of alcoholic drinks.
The main route of inactivation of ingested histamine is oxidative deamination of the primary amine group, catalysed by diamine oxidase (DAO), to give imidazole acetaldehyde.
The main function of DAO is to prevent histamine ingested through food from reaching the bloodstream via the intestine.
In addition to histamine, DAO can degrade other biogenic amines such as, for example, putrescine, spermidine and cadaverine. Its molecular weight is approximately 182 kDa with a carbohydrate proportion of 11%. It belongs to the class of amine oxidases that contain copper and catalyse oxidative deamination of primary amines to give aldehydes, ammonia and hydrogen peroxide. DAO uses molecular oxygen to oxidatively deaminate histamine to imidazole acetaldehyde, ammonia and hydrogen peroxide.

DAO is mainly found in the small intestine, liver, kidneys and blood leukocytes. Pregnant women have a blood DAO level of about 500 to 1000 times higher than non-pregnant women because DAO is also formed in the placenta. Histamine is continuously formed in the human body and excreted via the intestine, where it is degraded while passing through the intestinal mucosa by the DAO that is found there.
DAO is a sensitive enzyme that can be inhibited by various substances such as other biogenic amines, alcohol and by the degradation product acetaldehyde, and also by various medicines.
Apart from inhibition of DAO by certain types of substances, there is a significant percentage of the population whose blood DAO levels are abnormally low, which means that their blood histamine level is higher than values considered normal (2-20 micrograms/0.1 L). The high blood histamine levels in these types of subjects trigger a series of pathologies.
In this situation, preventative administration and treatment with supplementary DAO has the effect of contributing to degradation of excess histamine.
The present inventors have carried out clinical trials showing that treatment with supplementary DAO, which contributes to degradation of excess histamine, is very useful in the treatment or prevention of fibromyalgia or chronic fatigue (application ES 201130383), for blocking the effects of histamine release caused by consumption of alcoholic drinks and so preventing hangover symptoms (application ES 201130380) and for the treatment or prevention of diseases and pathological states associated with an elevated level of blood histamine that bring about an increase in pain, particularly in the treatment or prevention of migraine, fibromyalgia, spondylitis and muscle contractions (application 201130381).
The present inventors have found that approximately 80% of children with ADHD also show a congenital DAO activity deficiency, so they insufficiently metabolise ingested histamine, which passes to the blood. The problem is worsened by the fact that the majority of drugs that are prescribed in the treatment of ADHD are inhibitors of DAO activity. In principle these drugs improve the symptoms but in the long term the symptoms become chronic and create a dependency and requirement for higher doses, as the higher the medication the more DAO inhibition and more histamine passes into the bloodstream. Administration of DAO in children diagnosed with ADHD and DAO deficiency has been demonstrated to provide a significant improvement in the symptoms of attention deficit hyperactivity disorder.
U.S. Pat. No. 4,725,540 describes a method for the preparation of DAO from a DAO-producing microorganism such as Candida krusei or from a lactic acid producing bacterium in a nutrient medium, so that the DAO produced is able to degrade histamine at a pH of between neutral and approximately pH 4.
Patent application WO 02/43745 from 2001 describes the systemic use of DAO of vegetable origin for the treatment of diseases mediated by histamine, particularly for the treatment of allergies in general and anaphylactic reactions in particular. Pharmaceutical compositions comprising DAO as an active ingredient have also been described together with the corresponding doses and administration protocols. The DAO used is of plant origin. There has been no mention of the possible use of DAO compositions for the treatment or prevention of attention deficit hyperactivity disorder (ADHD).
Patent application WO 2006003213 from 2005 refers to pharmaceutical compositions for the treatment of diseases induced by histamine that comprise DAO of animal origin, presenting a composition for oral or peroral administration in an administration form protected against gastric acid. The compositions are particularly directed to the treatment of urticaria, atopic dermatitis and scombroid toxicity. In this patent application, the use of DAO of non-plant origin was preferred with the justification that this has the advantage that the allergens present in plants do not negatively influence the administration of this DAO because allergens essentially promote the release of endogenous histamine. The DAO used was preferably obtained from pig kidneys or by recombinant techniques. There has been no mention of the possible use of DAO compositions for the treatment or prevention of attention deficit hyperactivity disorder (ADHD).